Elucidation of mechanism for induction of pain with knockout mice

疼痛的感觉对受伤的发生提供了有用的警告。然而，在长期炎症、术后和神经损伤等病理条件下，外周的伤害感受器被激活，产生自发性疼痛、痛觉过敏和触觉痛（异常性痛）。我们之前证明了1)鞘内给药前列腺素（PG） E2和PGF2α诱导异位性疼痛，2)辣椒素敏感和不敏感通路参与异位性疼痛的诱导，3)PG可能通过启动突触末端谷氨酸释放→NMDA受体激活→NO生成的生化级联产生异位性疼痛。4) PGD2阻断pge2诱导的异常性疼痛。为了阐明某一特定成分是否参与敲除小鼠诱发异位性痛觉，我们在敲除小鼠中建立了部分坐骨神经结扎方法，得到如下结果。环加氧酶（cox）是生产PG的限速酶。COX-1是组成型，COX-2是诱导型，被认为是炎症中PG生成的原因。1)治疗1周后，COX-2^<-/->小鼠出现异位性疼痛，提示COX-2未参与异位性疼痛的诱导。2) COX-1选择性抑制剂能减轻坐骨神经损伤引起的疼痛反应，而COX-2选择性抑制剂不能。3) iNOS^<-/->小鼠出现异常性疼痛，NMDA^<-/->小鼠疼痛反应消失。这些结果表明，PGE2激活的谷氨酸兴奋传递在坐骨神经损伤后疼痛的诱导和维持中起关键作用。为了阐明异位性痛的诱导和维持，我们将对坐骨神经损伤模型进行扩展研究，并与i.t. PG异位性痛模型进行比较。

The sensation of pain provides useful warning about occurrence of injury. However, under pathological conditions such as prolonged inflammation, post-operation, and nerve injury, nociceptors in the periphery become activeted and produce spontaneous pain, hyperalgesia and tactile pain (allodynia). We previously demonstrated that 1) intrathecal administration of prostaglandin (PG) E2 and PGF2α induced allodynia, 2) capsaicin-sensitive and-insensitive pathways were involved in induction of allodynia, 3) PGs may produce allodynia by initiating a biochamical cascade of glutamate release from synaptic terminal→activation of NMDA receptor→NO production. 4) PGD2 blocked the PGE2-induced allodynia. In order to clarify the involvement of a given component in induction of allodynia by use of knockout mice, we established partial sciatic nerve ligation method in the knockout mouse and obtained following results.Cyclooxygenases (COXs) are rate-limiting enzymes for PG production. While COX-1 is a constitutive form, COX-2 is an inducible form and considered to be accounted for PG production in inflammation. 1) Although allodynia was induced 1 week after treatment, allodynia was observed in COX-2^<-/-> mice, suggesting that COX-2 was not involved in the induction of allodynia. 2) The COX-1 selective inhibitor, but not the COX-2 selective inhibitor, alleviated pain responses induced by sciatic nerve injury. 3) While allodynia was observed in iNOS^<-/-> mice, pain responses disappeared in NMDA^<-/-> mice. These results demonstrate that excitatory transmission by glutamate activated by PGE2 plays pivotal roles in induction and maintenance of pain following sciatic nerve injury. In order to elucidate the induction and maintenance of allodynia, we will extend this study of sciatic nerve injury model and compare it with that of i.t. PG allodynia model.